Since Charcot's first description, motor neurone disease (or amyotrophic lateral sclerosis) has remained an enigma.1 Without a clear understanding of the pathogenesis, and with relatively little therapy to offer other than symptomatic and palliative intervention, clinicians have faced the difficult task of effectively managing patients with this relentlessly progressive disease. However, advances in understanding over the past decade have reignited research interest, renewing hope that a curative approach may be forthcoming.

Motor neurone disease (MND) is characterised by progressive deterioration involving the corticospinal tract, brainstem and anterior horn cells of the spinal cord. Extraocular and sphincter muscles innervated by motor neurones not receiving direct projections from the motor cortex are characteristically spared. The term MND is used to encompass all forms of the disease, whatever the combination of upper and lower motor neurone involvement, while Americans still call it Lou Gehrig's disease, after the New York Yankees baseballer diagnosed with MND towards the end of his playing career.

The aetiology of MND is unknown but appears heterogeneous. Environmental factors may trigger a genetic susceptibility — toxins, chemicals, metals, previous infections, and trauma have all been proposed. Uncertainty about the aetiology often creates added concern in MND patients with regard to heritability, as highlighted by the Personal Perspective article in this issue of the Journal (page 344).2 Most aetiologies have been linked to a cascade involving the glutamatergic neurotransmitter system, with excessive activation of glutamate receptors at the synaptic cleft (excitotoxicity) eventually triggering destruction of motor neurones. In the rarer, familial type of MND, the breakthrough finding of a mutation involving the copper/zinc superoxide dismutase-1 (SOD1) gene3 (encoded on chromosome 21q22.1) has provided an impetus for MND research and suggested new therapeutic strategies. Mutations have subsequently been documented in a fifth of the approximately 5% of patients with familial MND. However, while SOD1 mutation screening is now clinically available, genetic counselling is critical before predictive testing is undertaken.

While MND is usually relentlessly progressive, with 50% of patients surviving fewer than three years from diagnosis, a smaller proportion of patients (about 20%) may survive between 5 and 10 years.4 Predominantly lower motor involvement tends to predict longer survival. In contrast, bulbar onset and respiratory compromise suggest a worse prognosis.

There remains no pathognomonic test for the diagnosis of MND. Physicians continue to rely on clinical criteria for diagnosis, specifically the presence of both upper motor neurone (spasticity, weakness and hyperreflexia) and lower motor neurone (fasciculation, wasting, weakness and hyporeflexia) signs. Fasciculations, an almost inevitable feature of MND, reflect spontaneous nerve activity, probably generated through upregulation of persistent sodium channels in dying motor axons.5 Clinical features, in combination with neurophysiological investigation, can confirm the diagnosis. Nerve conduction studies and electromyography may also be used to identify alternative, but potentially treatable, lower motor neurone disorders confined to motor fibres, particularly immune-mediated demyelinating neuropathies and multifocal motor neuropathy.6

While research criteria exist for diagnosis,7 these are rigorous and still rely on clinical findings to stratify the likelihood of diagnosis, with most patients considered as "possibly" or "probably" having MND before the diagnosis becomes "definite" with time. Although newer imaging techniques have shown promise in aiding diagnosis, the primary role of imaging is to exclude other conditions. Despite this clinically oriented approach, the reliability of diagnosis is high, demonstrated to be 90% when compared with autopsy findings.8

Confirming the diagnosis is devastating for the patient and family members and must be handled sensitively. Patients often complain that the diagnosis was conveyed in a hurried and inappropriate manner, with some told off-handedly "to go home and write their will". A follow-up appointment a few weeks later may be beneficial to answer questions not addressed at the initial consultation, and to provide further information about support networks, particularly the Motor Neurone Disease Association.

Management needs to be multidisciplinary, involving physiotherapists (mobility and prevention of contractures), speech therapists (communication aids and swallowing assessment), occupational therapists (maintaining function), social workers (counselling and organising home support), and dietitians (particularly with percutaneous endoscopic gastrostomy feeding), all coordinated by the supervising neurologist or physician, with the aim of collectively maximising function and alleviating symptoms.9 Involvement of palliative care services should occur early, anticipating patient needs (eg, implementation of home services) well in advance of deterioration, and later assisting with disease-related symptoms and psychosocial issues. The role of ventilatory support remains controversial: non-invasive ventilation may improve symptoms related to respiratory insufficiency without extending survival, while invasive support may extend survival in MND patients with severe disability.10

Riluzole, an inhibitor of glutamate release, is the first medication found to increase survival in MND patients (by 3–6 months in two large randomised trials).11 Recent retrospective analyses suggest greater benefit, but these data have been confounded by general improvements in the care of MND patients. Although licensed worldwide, riluzole was only recently made available in Australia, and is currently being reconsidered for listing by the Pharmaceutical Benefits Advisory Committee.

Many MND patients take a range of over-the-counter antioxidants, particularly vitamins C and E, based on promising experimental data, although there remains no sound clinical evidence concerning efficacy. Neurotrophic and immunomodulatory treatments likewise have shown little clinical benefit, while preliminary studies focusing on neuroprotective approaches (eg, with minocycline12) suggest promise. "Alternative" therapies, some offering unrealistic hope of cure, are universally unproven for MND, are often expensive, and carry the risk of potentially harmful effects.

New preventive and restorative approaches are being intensively explored, including the role of stem cells as vehicles to regenerate functional connections in motor pathways. After a century of limited progress, the identification of specific causal genes and the development of animal MND models offer realistic hope that new treatments will emerge.